Design paper
Design and Baseline Characteristics for the Aminoguanidine Clinical Trial in Overt Type 2 Diabetic Nephropathy (ACTION II)

https://doi.org/10.1016/S0197-2456(99)00024-0Get rights and content

Abstract

Advanced glycosylation endproduct (AGE) formation has been implicated in the development and progression of nephropathy in type 2 diabetes mellitus. In diabetic animals, aminoguanidine inhibits AGE-mediated cross-linking of proteins in vascular and renal tissue and slows the progression of renal disease. ACTION II is a randomized, double-blind, placebo-controlled trial comparing two dose levels of aminoguanidine with placebo on the progression of nephropathy in 599 type 2 diabetic patients with renal disease from 84 centers in the United States and Canada. The primary endpoint is time to doubling of serum creatinine concentration. Secondary endpoints include the effect of aminoguanidine on time to all-cause mortality, end-stage renal disease (ESRD), cardiovascular morbidity and mortality, rate of change in indices of renal function (iothalamate, Cockcroft and Gault [C&G] calculated creatinine and measured creatinine clearances), proteinuria, retinopathy, circulating and urinary AGE levels, and estimation of the relationship between plasma aminoguanidine concentrations and primary and secondary efficacy endpoints and adverse events. Progression of macrovascular disease was monitored and fundus photography performed. Type 2 diabetic patients aged 30 to 70 years were eligible for the trial if their blood pressure was ⩽180 mm Hg systolic and ⩽120 mm Hg diastolic, serum creatinine concentration ⩾1.0 mg/dL (in women) or ⩾1.2 mg/dL (in men), C&G clearance ⩾40 mL/min, and proteinuria ⩾500 mg/d with diabetic retinopathy or diabetic nephropathy on renal biopsy. Recruitment began in July 1995 and terminated in December 1996. The trial randomized a total of 599 subjects. At baseline, the mean (standard deviation [SD]) age was 58 (7.7) years, diabetes duration 16.5 (7.5) years, body mass index 32 kg/m2 (10–90% range 26–42), arterial blood pressure 105 (12) mm Hg, C-peptide concentration 2.55 (1.71) ng/mL, serum glucose concentration 201 (89) mg/dL, hemoglobin A1c 8.7% (1.6), serum creatinine concentration 1.6 (0.5) mg/dL, iothalamate clearance 52 (25) mL/min/1.73 m2, proteinuria 4.1 (4.2) g/d, triglycerides 259 (214) mg/dL, and LDL cholesterol 144 (40) mg/dL. Patients are 72% male, 68% white, 16% black, and 16% Asian American and Native American. At baseline, 76% were receiving concomitant angiotensin-converting enzyme (ACE) inhibitors and 43% lipid-lowering agents. Follow-up in ACTION II was scheduled to continue through December 1998, so that follow-up was to be 2 years after the date of randomization of the final enrolled patient. The trial in fact ended in March 1998. This trial will contribute to our understanding of the natural history of type 2 diabetes mellitus–associated nephropathy and determine whether aminoguanidine will slow the progression of established diabetic renal disease. Control Clin Trials 1999; 20:493–510

Introduction

The chronic hyperglycemia of type 2 diabetes mellitus can lead to long-term microvascular and macrovascular complications, including neuropathy, retinopathy, nephropathy, and accelerated atherosclerosis 1, 2. Tissue damage may result from excessive chemical interaction between glucose and proteins, resulting in the formation of advanced glycosylation endproducts (AGEs) 3, 4. AGEs arise from the nonenzymatic reaction of carbonyl groups of glucose with amino groups of structural proteins, such as basement membrane collagen. With time, early glycated products (Amadori products) undergo rearrangement and dehydration to form stable protein-bound adducts (AGEs) that can crosslink proteins. AGE-mediated formation of rigid cross-links with matrix proteins and trapping of soluble proteins and lipoproteins in vascular walls is thought to play an important role in the development of diabetic complications [5].

Diabetic patients have markedly higher serum AGE levels than nondiabetics, and AGE levels parallel the severity of diabetic nephropathy [6]. Glycated proteins can continue trapping and cross-linking proteins even in the presence of normoglycemia. Therefore, normalization of glucose in diabetes mellitus may not completely prevent the progression of complications.

Aminoguanidine is a nucleophilic hydrazine derivative that binds irreversibly to reactive intermediates of early glycated products, particularly 3-deoxyglucosone, and prevents AGE formation and AGE-induced protein cross-linking [7]. Aminoguanidine reduces glomerular basement membrane fluorescence, IgG trapping, and albuminuria and slows mesangial matrix expansion in the streptozotocin-induced diabetic rat (at oral dosages of 50 mg/kg/d and higher) 8, 9, 10, 11, 12, 13. The aim of the “Aminoguanidine Clinical Trial in Overt Type 2 Diabetic Nephropathy” (ACTION II) is to evaluate the efficacy and safety of two dose levels of aminoguanidine in preventing or slowing the progression of established diabetic nephropathy in patients with type 2 diabetes mellitus. The primary objective is to evaluate the effect of aminoguanidine on the time to doubling of serum creatinine concentration. The secondary objectives are to evaluate the effects of aminoguanidine on time to all-cause mortality, time to cardiovascular morbidity and mortality, time to end-stage renal disease (ESRD), rate of change in glomerular filtration rate by iothalamate clearance, Cockcroft & Gault (C&G) calculation and creatinine clearance in 24-hour urine, rate of change in serum creatinine concentration, change in 24-hour urine protein excretion (versus baseline), change in serum and urine AGE concentration (versus baseline), quality-of-life scores, and changes in diabetic retinopathy. The study will also allow estimation of the relationship between plasma aminoguanidine concentrations and the primary and secondary efficacy endpoints and adverse events. This report describes the design of ACTION II and presents selected baseline demographic and clinical characteristics of the randomized participants.

Section snippets

Population

The target study population consists of patients 30 to 70 years of age with type 2 diabetes mellitus and proteinuria at least 500 mg/d in the presence of either diabetic retinopathy or evidence, from renal biopsy, of diabetic nephropathy. Initial C&G-calculated creatinine clearance was equal to or greater than 40 mL/min with serum creatinine concentration at least 1.0 mg/dL in women and 1.2 mg/dL in men. Patients had systolic blood pressures ⩽180 mm Hg and diastolic blood pressures ⩽120 mm Hg

Baseline characteristics

ACTION II randomized 599 patients. Seventy-two percent of these patients were male, 68% were white, 16% were black, and 16% were Asian American or Native American. Seventy-six percent were receiving concomitant ACE inhibitors, 43% were receiving lipid-lowering medications, and 13% are current smokers. The mean (standard deviation) age of patients was 58 (7.7) years and duration of diabetes was 16.5 (7.5) years. Table 4 lists the clinical characteristics of randomized patients and Table 5 their

Summary

ACTION II will determine whether aminoguanidine, an inhibitor of AGE-mediated protein cross-linking, will slow the progression of established type 2 diabetic nephropathy. Additionally, the trial will gather important information regarding the natural history and effect of aminoguanidine on the complications of type 2 diabetes mellitus and its associated nephropathy. These data will encompass mortality, the frequency and severity of cardiovascular disease, progression of diabetic retinopathy,

Acknowledgements

We would like to thank Kim Hairston for her secretarial assistance. The past editor of this journal, Janet Wittes, PhD, was a member of the ESMC.

References (41)

  • Z Makita et al.

    Advanced glycosylation end product in patients with diabetic nephropathy

    N Engl J Med

    (1991)
  • D Edelstein et al.

    Mechanistic studies of advanced glycosylation end product inhibition by aminoguanidine

    Diabetes

    (1992)
  • T Soulis-Liparota et al.

    Retardation by aminoguanidine of development of albuminuria, mesangial expansion, and tissue fluorescence in streptozocin-induced diabetic rat

    Diabetes

    (1991)
  • D Edelstein et al.

    Aminoguanidine ameliorates albuminuria in diabetic hypertensive rats

    Diabetologia

    (1992)
  • S.T Crowley et al.

    Effects of nonenzymatic glycosylation of mesangial matrix on proliferation of mesangial cells

    Diabetes

    (1991)
  • Clinical Investigator's Brochure. Aminoguanidine Hydrochloride, (Alteon Inc. Internal Document) Revised September,...
  • E.J Lewis et al.

    The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy

    N Engl J Med

    (1993)
  • D.W Cockcroft et al.

    Prediction of creatinine clearance from serum creatinine

    Nephron

    (1976)
  • J.M Lachin et al.

    Evaluation of sample size and power for analyses of survival with allowance for nonuniform patient entry, losses to follow-up, noncompliance, and stratification

    Biometrics

    (1986)
  • National High Blood Pressure Education Program (NHBPEP) Working Group Report on Hypertension and Chronic Renal Failure....
  • Cited by (214)

    • Effect of crocin on glycated human low-density lipoprotein: A protective and mechanistic approach

      2023, Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy
    View all citing articles on Scopus
    View full text